This study includes two main components: the first screening phase and the second clinical intervention phase. During the screening phase, subjects with poor response to clozapine are carefully evaluated by chart-review and clinical assessment. Via chart-review, clinical data of diagnosis, disease course and previous treatment outcome, and concomitant psychotropic agents are obtained. Clinical phenomenology, including psychopathology, psychotic and mood symptoms severity and side effect of psychotropic medication are assessed by clinical interview and observation, which are conducted by experienced clinicians. Blood sample will be also obtained from the subjects for measuring the baseline clozapine drug level and extracting DNA for further analysis. Subjects fulfilling the criteria of treatment-resistant schizophrenia with poor response to adequate dose and duration of clozapine treatment are eligible for the clinical trial phase of 14-week randomized, placebo-controlled amisulpride add-on study. In this phase, subjects are randomly allocated to amisulpride augmentation treatment group and placebo treatment group. Subjects in the former group will receive clozapine and amisulpride combination treatment, while in the latter group will receive clozapine and placebo. Outcomes of clinical efficacy and safety are carefully evaluated by experienced and well-trained research stuffs in the 14 weeks of clinical study period.

All of the above studies will be conducted in four hospitals, including DOH Bali Psychiatric Hospital, DOH Tao-yan Psychiatric hospital, and the Ju-Shang Psychiatric Hospital. Subjects will be recruited from the chronic in-patient settings from these three hospitals.

Inclusion Criteria:

• DSM-IV diagnosed schizophrenic patients;
• Age between 18 and 60;
• Before treatment with clozapine, documented treatment failure of two antipsychotics for an adequate duration of 6 weeks and in a sufficient dose of 600 mg/day of chlorpromazine equivalents;
• Documented failure to show a satisfactory clinical response to an adequate clozapine treatment, defined as at least clozapine 300 mg/day for 3 months or a plasma drug level of 350ng/ml;
• At least moderately ill, defined as with a Clinical Global Impression (CGI) greater than 4 or PANSS total score greater than 75;
• Persistent positive psychotic symptoms, with rating scores of moderate or worse on at least two of four positive symptom items (delusion, conceptual disorganization, hallucinatory behavior, and suspiciousness/persecution) on Positive and Negative Syndrome Scale (PANSS);

Exclusion Criteria:

• Patients with concomitant treatment with lithium, anti-convulsants, antidepressants and other antipsychotic medication ;
• Patients with underlying severe medical illness, such as cardiovascular disease, cerebrovascular disease, bone marrow suppression or epilepsy;
• Patients with comorbid diagnosis of substance dependence;